PROJECT SUMMARY/ABSTRACT ! Posterior cortical atrophy (PCA), a variant of sporadic Alzheimer's disease (SAD), displays classic AD amyloid plaque and neurofibrillary tangle pathology but preferentially affects the occipital cortex and visual system. Our recent findings on neuronal genomic mosaicism (NGM) and DNA content variation (DCV) in SAD neurons (Bushman & Kaeser et al., eLIFE) may provide a mechanistic framework for understanding PCA through somatically acquired, pathogenic changes (e.g., genomic amplifications) that occur in some (not all) single cells. These changes include increased DCV, with average gains of over 200 megabase pairs, as well as mosaic APP CNVs in single SAD neurons. The current proposal is designed to understand the role of NGM in PCA. Over the next 3 years, we will test the hypothesis that PCA neurons are enriched in SAD-related forms of NGM including APP CNVs, preferentially increased in occipital over temporal and prefrontal cortex. Two Specific Aims will be pursued. Aim 1 will Assess DNA content variation (DCV) including APP CNVs in neurons from PCA vs. non-PCA SAD and non-diseased brains, and identify affected neuronal subtypes. This aim will provide an understanding of NGM at the level of cortical regions (e.g., occipital and parietal vs. frontal) and layers. Aim 2 will assess CNVs in other known AD genes and will identify novel CNVs showing mosaic alterations amongst occipital lobe PCA neurons. This aim could provide a mechanism for the neuroanatomical regions affected by PCA, via enrichment of one or more AD genes by NGM, and could also identify novel disease-related genes. Completion of both Aims will add a new facet to understanding PCA through NGM, with potential relevance to other SAD variants as well as possible therapeutic targets preferentially affected by NGM.